Extracorporeal membrane oxygenation (ECMO) is a life-saving intervention for patients with circulatory and/or pulmonary failure; however, the rate of complications remains high. ECMO induces systemic inflammation, which may activate and damage the endothelium, thereby causing edema and organ dysfunction. Advancing our understanding in this area is crucial for improving patient outcomes during ECMO. The goal of this review is to summarize the current evidence of the effects of ECMO on endothelial activation and damage in both animals and patients. PubMed and Embase databases were systematically searched for both clinical and animal studies including ECMO support. The outcome parameters were markers of endothelial activation and damage or (in)direct measurements of endothelial permeability, fluid leakage and edema. In total, 26 studies (patient n = 16, animal n = 10) fulfilled all eligibility criteria, and used VA-ECMO (n = 13) or VV-ECMO (n = 6), or remained undefined (n = 7). The most frequently studied endothelial activation markers were adhesion molecules (ICAM-1) and selectins (E- and P-selectin). The levels of endothelial activation markers were comparable to or higher than in healthy controls. Compared to pre-ECMO or non-ECMO, the majority of studies showed stable or decreased levels. Angiopoietin-2, von Willebrand Factor and extracellular vesicles were the most widely studied circulating markers of endothelial damage. More than half of the included studies showed increased levels when compared to normal ranges, and pre-ECMO or non-ECMO values. In healthy animals, ECMO itself leads to vascular leakage and edema. The effect of ECMO support in critically ill animals showed contradicting results. ECMO support (further) induces endothelial damage, but endothelial activation does not, in the critically ill. Further research is necessary to conclude on the effect of the underlying comorbidity and type of ECMO support applied on endothelial dysfunction.

Extracorporeal membrane oxygenation (ECMO) can be a life-saving intervention, but it is associated with high complication rates. ECMO induces systemic inflammation and endothelial hyperpermeability, thereby causing tissue edema, microcirculatory perfusion disturbances, and organ failure. This study investigated whether the inhibition of vascular endothelial protein tyrosine phosphatase (VE-PTP), a regulator of endothelial permeability, reduces extracorporeal circulation (ECC)-induced microvascular dysfunction. Rats were subjected to ECC after treatment with Razuprotafib (n = 11) or a placebo (n = 11), or they underwent a sham procedure (n = 8). Razuprotafib had no effect on the ECC-induced impairment of capillary perfusion, as assessed with intravital microscopy, nor did it influence the increased wet-to-dry weight ratio in kidneys, a marker of edema associated with ECC. Interestingly, Razuprotafib suppressed the ECC-induced increase in TNFα, whereas angiopoietin-2 even further increased, following the discontinuation of ECC. Circulating interleukin-6, ICAM-1, angiopoietin-1, and soluble Tie2 and tissue VE-PTP, Tie1, and Tie2 mRNA expression were not affected by Razuprotafib. Furthermore, Razuprotafib improved the PaO₂/FiO₂ ratio and reduced histopathological pulmonary interstitial inflammation following ECC compared to the placebo. To conclude, treatment with Razuprotafib did not improve ECC-induced microcirculatory perfusion disturbances nor renal edema.